Fused benzeneoxyacetic acid derivatives

ABSTRACT

Fused benzeneoxyacetic acid derivatives of the formula (I): ##STR1## or salts thereof possess an agonistic effect on the PGI 2  receptor and thus are useful for preventing and/or treating thrombosis, arteriosclerosis, ischemic heart diseases, gastric ulcer and hypertension. A, B, D, and R 1  are as defined in the specification.

This is a division of application Ser. No. 08/722,456 filed Sep. 27,1996, allowed Jun. 29, 1998, now U.S. Pat. No. 5,869,919, which is adivision of Ser. No. 08/334,395 filed Nov. 3, 1994, now U.S. Pat. No.5,589,496, which is a division of Ser. No. 07/997,492 filed Dec. 28,1992, now U.S. Pat. No. 5,389,666, the disclosures of which areincorporated herein by reference in entirety.

SUMMARY

This invention is related to fused benzeneoxyacetic acid derivatives.

More particularly, this invention is related to:

1) fused benzeneoxyacetic acid derivatives of the formula (I): ##STR2##wherein all the symbols are the same meaning as hereafter defined, andnon-toxic salts thereof and non-toxic acid addition salts thereof,

2) processes for the preparation thereof, and

3) pharmaceutical agents containing them as active ingredient.

BACKGROUND OF THE INVENTION

Prostaglandin I₂ (PGI₂) is a physiologically active natural substancehaving the following structural formula, which is biosynthesized fromProstaglandin H₂ (PGH₂) in the metabolic process in vivo calledarachidonate cascade. ##STR3## (see Nature, 263, 663(1976),Prostaglandins, 12, 685(1976), ibid, 12, 915(1976), ibid, 13, 375(1977)and Chemical and Engineering News, Dec. 20, 17(1976).

PGI₂ has been confirmed to possess not only a very strong inhibitoryactivity on blood platelet aggregation but a dissociative activity onblood platelet aggregation, an inhibitory activity on blood plateletadhesion, a vasodilating activity, an inhibitory activity on gastricacid secretion etc. Therefore, it has been considered that PGI₂ isuseful for the prevention and/or the treatment for thrombosis,arteriosclerosis, ischemic heart diseases, gastric ulcer, hypertensionetc. But its application for pharmaceuticals is limited because of itschemical instability and difficulty of separation of the actionsaccording to purpose. Accordingly, various PGI₂ derivatives have beensynthesized and many researches have been carried out for themaintenance and the separation of the actions. However, we have notnecessarily satisfactory results yet.

Recently, in order to solve two problems above described, the researchfor PGI2 receptor agonists which have a new-typed skeleton and may beuseful for the treatment of or for the prevention of the above diseases,in view of PGI₂ receptor level, has been carried out.

RELATED ARTS

It has been reported in the literatures, that the following compoundsnot having the PGI2 skeleton are PGI₂ receptor agonists which bind to aPGI₂ receptor and inhibit blood platelet aggregation: ##STR4## (seeBrit. J. Pharmacol., 76, 423(1982), ibid, 84, 595(1985), and theJapanese Patent Kohyo No. 55-501098), ##STR5## (see Brit. J. Pharmacol.,76, 423(1982), ibid, 84, 595(1985), and the Japanese Patent Kohyo No.57-501127), and ##STR6## (see Brit. J. Pharmacol., 102, 251-266(1991)and the West Germnan Patent Publication No. 3,504,677).

PURPOSE OF THE INVENTION

Energetic investigations have been carried out in order to discover newPGI₂ receptor agonists having a skeleton in chemical structure differentfrom the compounds mentioned above, the present inventors have foundthat a kind of fused benzeneoxyacetic acid derivatives has an activityon binding to PGI₂ receptor and an inhibitory activity on blood plateletaggregation, and have accomplished the present invention.

The fused benzeneoxyacetic acid derivatives of the formula (I), of thepresent invention are quite novel, and it is not easy to predict fromthe above compounds already known as PGI₂ receptor agonist, that thecompounds of the present invention have an activity of PGI₂ receptoragonist.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to:

1) fused benzeneoxyacetic acid derivatives of the formula (I): ##STR7##R¹ is (i) hydroxy,

(ii) C₁₋₁₂ alkoxy or

(iii) NR² R³ ;

R² and R³ each, independently, is

(i) hydrogen atom or

(ii) C₁₋₄ alkyl; or

R² and R³, taken together with nitrogen atom bond to R² and R³ are theresidue of an amino acid;

R⁴ each, independently, is

(i) hydrogen atom,

(ii) C₁₋₄ alkyl,

(iii) phenyl or

(iv) C₁₋₄ alkyl substituted by one or two ring optionally selected from4-7 membered monocyclic hetero ring containing one or two nitrogen atom,and phenyl;

the said phenyl and hetero rings may also be substituted by one to threeof C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen atom, nitro or trihalornethyl, whenR⁴ is phenyl or the group containing phenyl or 4-7 membered monocyclichetero ring containing one or two nitrogen atom,

Y is oxygen atom or sulfur atom;

e is 3-5;

f is 1-3;

l is 1-3;

m is 1 or 2;

p is 1-4;

q is 0-2;

r is 1-4;

s is 0-3;

with the proviso that,

(1) when A is ##STR8## wherein all the symbols are the same meaninghereinbefore defined, or ##STR9## wherein R⁴ is hydrogen atom,

q or s is not zero;

(2) when A is ##STR10## wherein Y, l and m are the same meaning ashereinbefore defined, and R⁴ is C₁₋₄ alkyl substituted by hetero ring, ahetero ring in R⁴ should be bonded to the alkyl via a carbon atom in thehetero ring;

(3) --(CH₂)_(r) -- or ═CH--(CH₂)_(s) -- should be bonded to the carbonatom at the position a or b in the ring;

(4) when A is ##STR11## wherein R⁴ is the same meaning as hereinbeforedefined, ##STR12## in which p and e are the same meaning as hereinbeforedefined; and non-toxic salts thereof and non-toxic acid addition saltsthereof;

2) processes for the preparation thereof and

3) pharmaceutical agents containing them as active ingredient.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy, alkylene and alkenylene includestraight and branched ones. Double bond in alkenylene includes E, Z andEZ mixture. Isomers generated by asymmetric carbon atoms, e.g., branchedalkyl are included in the present invention.

The compounds of the formula (I) of the present invention, wherein R¹ ishydroxy may be converted into the corresponding salts by methods knownper se. Non-toxic and water-soluble salts are preferable. Suitablesalts, for example, are salts of alkaline metal (potassium, sodiumetc.), salts of alkaline earth metal (calcium, magnesium etc.), ammoniumsalts, salts of pharmaceutically-acceptable organic amine(tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris (hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine etc.).

The compounds of the formula (I) may be converted into the correspondingacid additional salts by methods known per se. Non-toxic andwater-soluble salts are preferable. Suitable acid addition salts, forexample, are salts of inorganic acids, e.g., hydrochloride,hydrobromide, sulphate, phosphate, nitrate etc., or salts of organicacids, e.g., acetate, lactate, tartarate, oxalate, fumarate, maleate,citrate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, toluenesulphonate, isethioate, glucuronate, gluconateetc.

The compounds of the formula (I), salts thereof or acid additional saltsthereof may be converted into hydrate thereof by methods known per se.

In the formula (I), C₁₋₁₂ alkoxy represented by R¹ means methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy,nonyloxy, decyloxy, undecyloxy, dodecyloxy and isomers thereof. C₁₋₄alkyl represented by R², R³ and R⁴, means methyl, ethyl, propyl, butyland isomers thereof.

In the formula (I), 4-7 membered monocyclic hetero ring containing oneor two nitrogen atom represented by R⁴ means pyrrole, pyridine, azepine,imidazole, pyrazole, pyrazine, pyrimidine, pyradazine, diazepine andpartially or fully saturated ring thereof.

C₁₋₄ alkyl as substituents of a phenyl or hetero ring in the groprepresented by R⁴ mean methyl, ethyl, propryl, butyl and isomersthereof. C₁₋₄ alkoxy mean methoxy, ethoxy, propoxy, butoxy and isomersthereof.

Halogen atom and halogen atom in trihalomethyl mean fluorine, chlorine,bromine and iodine atoms.

Example of representative compounds of the formula (I), of the presentinvention are listed as follows:

2-(Imidazol-1-yl)methyl-2,3-dihydroinden-4-yloxy! acetic acid,

1-2-(4-Phenylmethylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1-3-(4-Phenylmethylimidazol-1-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1- 2-(4-Phenylmethylimidazol-1-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(4-Phenylmethylimidazol-1-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(1-Diphenylmethylimidazol-2-yloxy)methyl-1,2,3,4-tetrahydronaphthalen-6-yloxy!acetic acid,

2-3-(1-Diphenylmethylimidazol-2-yloxy)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(1-Diphenylmethylimidazol-2-yloxy)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(1-Diphenylmethylimidazol-2-yloxy)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-Diphenylmethylimidazol-2-ylthio)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-3-(4-Diphanylmethylimidazol-2-ylthio)-1-propeny!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-Diphenylmethylimidazol-2-ylthio)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(4-Diphenylmethylimidazol-2-ylthio)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-2-(2-Oxo-4-diphenylmethylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-3-(2-Oxo-4-diphenylmethylimidazol-1-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-2-(2-Oxo-4-diphenylmethylimidazol-1-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(2-Oxo-4-diphenylmethylimidazol-1-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(3,4,5-Triphenylpyrazol-1-yl)methylbenzocycloheptan-6-yloxy! aceticacid,

2-4-((3-Chlorophenyl)phenylmethyl)pyrazol-2-yl!methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 3-4-((3-Chlorophenyl)phenylmethyl)pyrazol-2-yl!-1-propeny!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-4-((3-Chlorophenyl)phenylmethyl)pyrazol-2-yl!methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1- 2- 4-((3-Chlorophenyl)phenylmethyl)prazol-2-yl!ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid,

2-3-((4-Diphenylmethyl)-1,2,3-triazol-2-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-((4-Diphenylmethyl)-1,2,3-triazol-1-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-((4-Diphenylmethyl)-1,2,3-triazol-3-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(1,2,4-Oxadiazin-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-2-(1,2,4-Oxadiazin-5-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(1,2,4-Oxadiazin-5-yl)methyl-3,4-dihydronaphthalen-5-yloxy! aceticacid,

1-2-(1,2,4-Oxadiazin-5-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 3-(3-Phenyl-1,2,4-oxadiazol-5-yl)propyl!-2,3-dihydroinden-4-yloxy!acetic acid,

2- 2-(Oxazol-2-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy! aceticacid,

2- 2-(Oxazol-2-yl)ethenyl!-1,2,3,4-tetrahydronaphthaien-5-yloxy! aceticacid,

2- 2-(Oxazol-2-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy! acetic acid,

1- 2-(Oxazol-2-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 2-4-(3-Trifluoromethylphenyl)oxazol-2-yl!ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 2-4-(3-Trifluoromethylphenyl)oxazol-2-yl!ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 2-4-(3-Trifluoromethylphenyl)oxazol-2-yl!ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1- 2-4-(3-Trifluoromethylphenyl)oxazol-2-yl!ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1- 2-(Oxazol-4-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy! aceticacid,

1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1-2-(3-Nitrophenyl)oxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1-2-(2-(3-Nitrophenyl)oxazol-4-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

1-2-(3-Nitrophenyl)oxazol-4-yl)methyl-3,4-dihydronaphthalen-5-yloxy!aceticacid,

1-2-(2-(3-Nitrophenyl)oxazol-4-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(Imidazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy! aceticacid,

2-(2-(Imidazol-4-yl)ethenyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(Imidazol-4-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-(2-(Imidazol-4-yl)ethylidene)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2- 3- 4-((1-Imidazolyl)phenylmethyl)pyrazol-2-yl!-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid,

2-4-((1-Imidazolyl)phenylmethyl)pyrazol-2-yl!methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1- 2- 4-((1-Imidazolyl)phenylmethyl)pyrazol-2-yl!ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid,

1- 3-(5-Diphenylmethyl-1,2,4-oxadiazol-3-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid,

1-2-(5-Diphenylmethyl-1,2,4-oxadiazol-3-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1- 2-(5-Diphenylmethyl-1,2,4-oxadiazol-3-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid,

2-2-(5-Diphenylmethylisoxazol-3-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(5-Diphenylmethylisoxazol-3-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(5-Diphenylmethylisoxazol-3-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-2-(3-Diphenylmethylisoxazol-5-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(3-Diphenylmethylisoxazol-5-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid,

1-2-(3-Diphenylmethylisoxazol-5-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((3-Pyrrolyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthaien-5-yloxy!acetic acid,

2-(4-((2-Imidazolyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((4-Pyrazolyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-(Di(3-pyridyl)methyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((3-Pyrimidinyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((2-Pyrazinyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((4-Pyridazinyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((3-Azepinyl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

2-(4-((1,3-Diazepin-5-yl)phenylmethyl)pyrazol-1-yl)methyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,

and those described in examples below, and further, non-toxic saltsthereof and non-toxic acid addition salts thereof.

Processes for the Preparation of the Compounds of the Present Invention

In the compounds of the present invention, of the formula (I),

(1) compounds of the formula (I-1): ##STR13## wherein A¹ is the samemeaning as A, with the proviso that, in the group represented by R⁴ inA, a hetero ring as a substituent of C₁₋₄ alkyl should be bonded to thealkyl via a carbon atom in the hetero ring, and the other symbols arethe same meaning as hereinbefore defined, may be prepared:

(A) by reacting a compound of the formula (III): ##STR14## whereinR^(1a) is methoxy or ethoxy and the other symbols are the same meaningas hereinbefore defined, with the compound of the formula (a)

    HA.sup.a                                                   (a)

wherein A^(a) is ##STR15## wherein all the symbols are the same meaningas hereinbefore defined, (B) by reacting a compound formula (III):##STR16## wherein all the symbols are the same meaning as hereinbeforedefined, with an oxazole,

(C) by the cyclization of a compound of the formula (V): ##STR17##wherein all the symbols are the same meaning as hereinbefore defined,(D) by reacting a compound of the formula (VIII): ##STR18## whereinR^(4a) is (i) C₁₋₄ alkyl, (ii) phenyl or (iii) C₁₋₄ alkyl substituted byone or two ring optionally selected from 4-7 membered monocyclic heteroring containing one or two nitrogen atom, and phenyl, and the othersymbols are the same meaning as hereinbefore defined, with the compoundof the formula (b):

    BrCH.sub.2 COR.sup.1a                                      (b)

wherein R^(1a) is the same meaning as hereinbefore defined,

(E) by reacting a compound of the formula (IX): ##STR19## wherein allthe symbols are the same meaning as hereinbefore defined, with thecompound of the formula (b):

    BrCH.sub.2 COR.sup.1a                                      (b)

wherein R^(1a) is the same meaning as hereinbefore defined,

(F) by reacting a compound of the formula (XI): ##STR20## wherein allthe symbols are the same meaning as hereinbefore defined, with thecompound of the formula (c):

    R.sup.4 COCl                                               (c)

wherein R⁴ is the same meaning as hereinbefore defined,

(G) by reacting a compound of the formula (XII): ##STR21## wherein allthe symbols are the same meaning as hereinbefore defined, with thecompound of the formula (d): ##STR22## wherein R⁴ is the same meaning ashereinbefore defined, (H) by the cyclization of a compound of theformula (XIV): ##STR23## wherein all the symbols are the same meaning ashereinbefore defined, (I) by reacting a compound of the formula (XVI):##STR24## wherein all the symbols are the same meaning as hereinbeforedefined, with the compound of the formula (b):

    BrCH.sub.2 COR.sup.1a                                      (b)

wherein R^(1a) is the same meaning as hereinbefore defined,

(J) by reacting a compound of the formula (XIX): ##STR25## wherein allthe symbols are the same meaning as hereinbefore defined, with thecompound of the formula (b):

    BrCH.sub.2 COR.sup.1a                                      (b)

wherein R^(1a) is the same meaning as hereinbefore defined,

(K) by reacting a compound of the formula (XX): ##STR26## wherein allthe symbols are the same meaning as hereinbefore defined, with thecompound of the formula (b):

    BrCH.sub.2 COR.sup.1a                                      (b)

wherein R^(1a) is the same meaning as hereinbefore defined,

(L) by the hydrolysis of an ester bond in a compound of the formula(Ia): ##STR27## wherein all the symbols are the same meaning ashereinbefore defined, (M) by subjecting a compound of the formula (Ib):##STR28## wherein all the symbols are the same meaning as hereinbeforedefined, to form an acyl chloride, and then by the reaction of thecompound thus obtained with the compound of the formula (f):

    R.sup.1b OH                                                (f)

wherein R^(1b) is C₃₋₁₂ alkyl or

(N) by subjecting a compound of the formula (Ib): ##STR29## wherein allthe symbols are the same meaning as hereinbefore defined, to form anacyl chloride, and then by the reaction of the compound thus obtainedwith the compound of the formula (g):

    HNR.sup.2 R.sup.3                                          (g)

wherein R² and R³ are the same meaning as hereinbefore defined.

The reaction (A) may be carried out in an appropriate organic solvent(e.g., dimethylformamide) in the presence of an appropriate base (e.q.,sodium hydride).

The reaction (B) may be carried out in an appropriate organic solvent(e.g., tetrahydrofuran) in the presence of an appropriate base (e.q.,n-butyllithium).

The reaction (C) and (H) may be carried out in an appropriate organicsolvent (e.g., toluene) at 20° C.

The reaction (D), (E), (I), (J) and (K) may be carried cut in anappropriate organic solvent (e.g., acetone) in the presence of anappropriate base (e.q., potassium carbonate).

The reaction (F) may be carried out at 100° C.

The reaction (G) may be carried out in an appropriate organic solvent(e.g., chloroform) at 70° C.

The reaction (L) may be carried out in an appropriate solvent (e.g.,methanol, tetrahydrofuran), using a hydroxide or a carbonate of analkaline metal.

The reaction (M) and (N) may be carried out by reacting a compound ofthe formula (Ib) with an acyl halide such as oxalyl chloride, thionylchloride in an appropriate solvent (e.g., methylene chloride), and thenby reacting a compound thus obtained with an alcohol of the formula (f)and an amine of the formula (g), respectively, in an appropriate solvent(e.g., methylene chloride), in the presence of an appropriate base(e.q., triethylamine) at 0 to 40° C.

The compounds of formulae (III), (V), (VIII), (IX), (XI), (XII), (XIV),(XVI), (XIX), (XX), (Ia) and (Ib) may be prepared by using a series ofreactions depicted in the following scheme.

The compounds of the formulae (a), (b), (c), (d), (f) and (g) are wellknown per se, and may be obtained commercially as reagents or may beeasily prepared by methods known per se. ##STR30## In the scheme,

R^(4d) is

(i) hydrogen atom,

(ii) C₁₋₄ alkyl,

(iii) phenyl or

(iv) C₁₋₄ alkyl substituted by one or two rings optionally selected from4-7 membered monocyclic hetero ring containing one or two nitrogen atomor phenyl and/or one hydroxy;

R^(4e) is the same meaning as R^(4d) provided that the hydroxy in R^(4d)should be replaced by --OLi;

DMF is N,N-dimethylformamide;

TEA is triethylamine;

DHP is dihydropyran;

THP is tetrahydropyran-2-yl;

DME is dimethoxyethane;

TBAB is tetra-n-butylammonium bromide;and the other symbols are the samemeaning as hereinbefore defined.

The compounds of the formulae (j), (k) and (l) are well known per se,and may be obtained commercially as reagents or may be prepared bymethods known per se from commercially available reagents.

(2) In the compound of the present invention, of the formula (I),compounds of the formula (I-2); ##STR31## wherein A² is ##STR32##wherein R⁴ is the same meaning as hereinbefore defined, with the provisothat, a hetero ring as a substituent of C₁₋₄ alkyl should be bonded tothe alkyl via a nitrogen atom in the hetero ring, and at least one groupin R⁴ is the alkyl substituted by a hetero ring, and the other symbolsare the same meaning as hereinbefore defined, may be prepared:

(A) by subjecting a compounds of the formula (XIII): ##STR33## whereinA^(b) is ##STR34## wherein R^(4b) each independently, is

(i) hydrogen atom,

(ii) C₁₋₄ alkyl,

(iii) phenyl,

(iv) C₁₋₄ alkyl substituted by one or two of phenyl or ketone, the saidphenyl may be also substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen atom,nitro or trihalomethyl, when R^(4b) is phenyl or the group containingphenyl;

at least one in R^(4b) is C₁₋₄ alkyl substituted by ketone and the othersymbols are the same meaning as hereinbefore defined,

to a series of reactions of (1) hydrolysis→(2) reduction→(3)esterification→(if desired (4) mesylation)→(5) reaction with a compoundof the formula (i):

wherein R^(4c) is 4-7 membered monocyclic hetero ring containing one ortwo nitrogen atom, or haloid acid thereof,

(B) by subjecting a compound of the formula (Ic): ##STR35## wherein allthe symbols are the same meaning as hereinbefore defined, to the sameprocedure as method hereinbefore described in (L), (M) or (N) for thepreparation of the compound of the formula (I-1) from those of formula(Ia) or (Ib).

The reaction (5) in (A) carried out in an appropriate organic solvent(e.q., dimethylformamide) at 110° C.

The compounds of the formulae (XIII) and (Ic) may be prepared by using aseries of reactions depicted in the following scheme. ##STR36##

In the scheme, all the symbols are the same meaning as hereinbeforedefined, and the compounds of the formulae (h) and (i) are well knownper se, or may be prepared by methods known per se.

In each reaction in the present specification, products may be purifiedby conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

Starting materials and each reagents in the present specification arewell known per se, or may be prepared by methods known per se.

For example, the processes for the preparation of the compounds of theformula: ##STR37## in the compounds of the formula (II), the compoundsof the formula: ##STR38## in the compounds of the formula (VI), thecompounds of the formula: ##STR39## in the compounds of the formula (X)and the compounds of the formula: ##STR40## in the compound of theformula (XVII) are described in the specification of the Japanese PatentApplication No. 3-130467.

The process for the preparation of the compounds of the formula:##STR41## in the compounds of the formula (VI) is described in thespecification of the Japanese Patent Application No. 3-322612.

The compounds of the formula (XV) may be prepared by methods known perse from the compound of the formula (IV) in described above.

Pharmacological Activities

It has been confirmed that the compounds of the present invention of theformula (I) possess an agonistic activity on PGI₂ receptor by thefollowing experimental results.

i) Inhibitory activity on binding of ³ H-iloprost to PGI₂ receptor onhuman blood platelet membrane fraction Method

50 mM Tris-HCl buffer (pH 7.4) containing 15 mM MgCl₂, 5 mM EDTA and 10nM ³ H!-iloprost were used as reaction medium. To 0.2 ml of the reactionmedium, human blood platelet membrane fraction (0.3 mg protein) wasadded with or without a test compound. The mixture was incubated at 24°C. for 30 min. After incubation, 4 ml of ice-cold 10 mM Tris-HCl buffer(pH 7.4) was added to the reaction mixture, and filtered through WhatmanGF/B glass fiber filter, and washed 4 times with 4 ml of ice-cold 10 mMTris-HCl buffer (pH 7.4) to separate bound and free ³ H!-iloprost. Afterwashing, the filter was dried and radioactivity was counted.Non-specific binding was obtained by performing parallel bindingexperiments in the presence of 10 μM non-labelled iloprost. Specificbinding was calculated by subtracting the non-specific binding from thetotal binding.

The inhibitory effect of test compound was calculated from the followingequation.

    The percentage of inhibition (%)=100-(B.sub.1 /B.sub.0 ×100)

B₁ : specific ³ H!-iloprost binding in presence of test compound

B₀ : specific ³ H!-iloprost binding in absence of test compound

The results are shown in the following table 1.

                  TABLE 1    ______________________________________           EX. No.                 IC.sub.50 (μM)    ______________________________________           2     0.043           2(a)  2.3           2(c)  3.9           2(d)  6.8           2(e)  2.6           2(g)  0.35           2(h)  0.36           2(i)  0.21           4(b)  5.0           4(c)  8.2           4(f)  1.4           6     5.0           6(b)  4.0           6(c)  0.058           8     2.0           8(a)  0.26           10    1.8           12    0.32           14    0.94           16    6.8           22    0.018           22(a) 0.16           24    8.0    ______________________________________

ii) Inhibitory effect on human blood platelet aggregation Method

Platelet-rich plasma (PRP) was prepared from human blood (5×10⁵platelets / mm³), and a test compound was added to PRP 1 min prior tothe addition of ADP (4 μm). The aggregation was monitored using aplatelet aggregometer (NBS HEMA TRACER 601, Niko Bioscience, Japan). Theresults are shown in the following table 2.

                  TABLE 2    ______________________________________           EX. No.                 IC.sub.50 (μM)    ______________________________________           2     0.045           2(a)  13           2(c)  12           2(d)  20           2(e)  15           2(g)  0.30           2(i)  0.15           4(b)  11           6(b)  16           8(a)  1.0           10    5.1           12    1.0           14    1.6           16    12           22    0.093    ______________________________________

Toxicity

The toxicity of the compounds of the present invention, of the formula(I) is very low and therefore, it may be confirmed that the compounds ofthe present invention are fully safe for pharmaceutical use.

Application for Pharmaceuticals

The compounds of the present invention, of the formula (I) possess anagonistic activity on PGI₂ receptor, and therefore are useful for theprevention and/or the treatment of thrombosis, arteriosclerosis,ischemic heart diseases, gastric ulcer and hypertension, etc.

For the purpose above described, the compounds of the formula (I), ofthe present invention, non-toxic salts thereof, acid additional saltsthereof and hydrates thereof may be normally administered systemicallyor partially, usually by oral or parenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 100μg and 100 mg, by parenteral administration up to several times per day,or continuous administration between 1 and 24 hrs. per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

When administration of the compounds of the present invention, it isused as solid compositions, liquid compositions or other compositionsfor oral administration, as injections, liniments or suppositories etc.for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules. Capsules includehard capsules and soft capsules.

In such compositions, one or more of the active compound(s) is or areadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.). Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (such asmagnesium stearate etc.), disintegrating agents (such as cellulosecalcium glycolate, etc.), stabilizing agents (such as lactose, etc.),and assisting agents for dissolving (such as glutamic acid, asparaginicacid etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate etc.), or be coated with morethan two films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs. In such compositions, one or more of the active compound(s)is or are contained in inert diluent(s) commonly used in the art(purified water, ethanol etc.). Besides inert diluents, suchcompositions may also comprise adjuvants (such as wetting agents,suspending agents, etc.), sweetening agents, flavouring agents,perfuming agents, and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g. stabilizing agents (sodium,sulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citricacid, etc.). For preparation of such spray compositions, for example,the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 (hereinincorporated in their entireties by reference) may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one more of active compound(s) is or are admixed with at least one ofinert aqueous diluent(s) (distilled water for injection, physiologicalsalt solution etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSORBATE80 (registered trademark)etc.).

Injections may comprise additional other than inert diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent (lactose etc.), assisting agents such asassisting agents for dissolving (glutamic acid, asparaginic acid etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They may also be manufactured in theform of sterile solid compositions, for example, by freeze-drying, andwhich may be dissolved in sterile water or some other sterile diluent(s)for injection immediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments, ointment, suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by per se known methods.

REFERENCE EXAMPLE AND EXAMPLES

The following reference examples and examples are intended toillustrate, but not limit, the present invention.

The solvents in parentheses show the developing or eluting solvents andthe ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" was measured by KBr method, "NMR" wasmeasured in a solution of CDCl₃, "mp." means melting point, and "MS"means mass spectrum.

Reference Example 1 Methyl(2-bromomethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy) acetate ReferenceExample 1 ##STR42##

To a solution of methyl(2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy) acetate (4.19 g)in methylene chloride (80 ml) were successively added triphenylphosphine(6.61 g) and carbon tetrabromide (11.1 g) at room temperature. Themixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=9:1) to give the title compound (4.58 g) having the followingphysical data.

IR (cm⁻¹): ν 2927, 2849, 1762, 1605, 1586, 1467, 1437, 1376, 1345, 1283,1206, 1120, 1003, 766, 710.

Reference Example 2 1-Benzyl-4-ethoxycarbonylpyrazole ##STR43##

To a suspension of sodium hydride (containing 63%, 652 mg) indimethylformamide (abbreviated as DMF hereinafter) was added a solutionof 4-ethoxycarbonylpyrazole (2.00 g) in DMF (15 ml) at room temperature.After stirred for 30 min at room temperature, to the mixture was addedbenzylbromide (2.04 ml). After stirred for 30 min, the mixture wasquenched by addition of water. The mixture was extracted with ethylacetate - n-hexane. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=3:1) to give the title compound (2.98 g) havingthe following physical data.

TLC: Rf 0.27 (ethyl acetate: n-hexane=1:3);

IR (cm⁻¹): ν 3122, 2973, 1714, 1555, 1457, 1373, 1350, 1307, 1224, 1192,1115, 1027, 988, 881, 771, 706, 621.

Reference Example 3 1-Benzyl-4-diphenylhydroxymethylpyrazole ##STR44##

To a solution of the compound prepared in reference example 2 (2.85 g)in tetrahydrofuran (THF, 30 ml) was added phenylmagnesium bromide (61.9m mol) at 0° C. After stirred for 1 h at room temperature, the mixturewas quenched by addition of ice and an aqueous solution of ammoniumchloride. The mixture was extracted with ethyl acetate--n-hexane (1:2).The extract was washed with water and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfate,and evaporated. The residue was purified by silica gel columnchromatography (ethyl acetate: n-hexane=2:5) to give the title compound(1.31 g) having the following physical data.

TLC: Rf 0.48 (ethyl acetate: n-hexane=1:1);

IR (cm⁻¹): ν 3242, 3062, 3030, 2929, 1601, 1553, 1495, 1449, 1387, 1332,1160, 1030, 1001, 879, 808, 757, 729, 700, 529.

Reference Example 4 4-Diphenylmethylpyrazole ##STR45##

To a mixture of small piece of sodium (1.5 g) in liquid ammonia (30 ml)was added a solution of the compound prepared in reference example 3(1.3 g) in THF (10 ml) at -78° C. The mixture was stirred at -70° C. inthe beginning, and the temperature of the mixture was raised graduallyto -25° C. over 3 h. The mixture was quenched by addition of ammoniumchloride (1.5 g). The mixture was warm up to room temperature and excessammonia was removed. The residue was diluted with water, and extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate: n-hexane =2:1→1:0) to give the title compound having thefollowing physical data.

TLC: Rf 0.40 (ethyl acetate: n-hexane=1:1);

IR (cm⁻¹): ν 3120, 3024, 2946, 1601, 1490, 1451, 1391, 1362, 1144, 1078,1052, 1032, 1007, 953, 879, 824, 750, 734, 699, 663, 636, 506, 476.

Reference Example 5 1.1-Diphenyl-2-amino-hydroxyiminoethane ##STR46##

A mixture of diphenylacetonitrile (7.0 g), hydroxylamine hydrochloride(3.03 g), and sodium acetate (6.67 g) in 150 ml of 5:1 ethanol-water wasrefluxed for 4 h. The mixture was concentrated under reduced pressure.The residue was triturated with water, filtrated, and dried to give thetitle compound (2.5 g) having the following physical data.

NMR: δ7.40-7.00 (10H, m), 5.55 (2H, brs), 4.88 (1H, s), 4.57 (1H, brs);

IR (cm⁻¹): ν 3481, 3371, 3196, 1668, 1575, 1492, 1452, 1359, 1084, 1030,959, 933, 863, 725, 704, 633.

Reference Example 6 Methyl 1-2-(1-amino-2,2-diphenylethylidene)aminoxycarbonylethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR47##

A stirred suspension of3-(5-methoxycarbonylmethyl-1,2,3,4-tetrahydronaphthalen-1-yl) propionicacid (300 mg) and oxalyl chloride (5.0 ml) was refluxed for 1 h. Themixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved into methylene chloride (10 ml). Thesolution was added dropwise to an ice bath-cooled solution of1,1-diphenyl-2-amino-2-(hydroxyimino)ethane (279 mg) prepared inreference example 5 and triethylamine (0.29 ml) in methylene chloride(3.0 ml). After the addition of the solution was completed, the mixturewas stirred for 1 h at room temperature. The mixture was diluted withethyl acetate. The extract was washed with water, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (n-hexane: ethyl acetate=3:2) to give thetitle compound (447 mg) having the following physical data.

MS (m/z): 501 (M⁺ +1);

IR (cm⁻¹): ν 3493, 3370, 2944, 1737, 1617, 1581, 1494, 1456, 1367, 1338,1274, 1164, 1130, 1081, 1003, 872, 783, 702, 640.

Reference Example 72-Carboxymethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene ##STR48##

A mixture of2-methoxycarbonylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g)and pyridine hydrochloride (40 g) was stirred for 2 h at 190° C. Themixture was cooled to room temperature, dissolved into water. Themixture was extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, and evaporated to give the title compound having thefollowing physical data. The obtained residue was used for the next stepwithout purification.

NMR: δ8.38 (1H, brs), 6.92 (1H, t, J=8 Hz), 6.64 (1H, d, J=8 Hz), 6.57(1H, d, J=8 Hz), 2.98-2.78 (2H, m), 2.67-1.91 (7H, m), 1.54-1.30 (1H,m).

Reference Example 82-Methoxycarbonylmethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene##STR49##

To a solution of thionyl chloride (5.0 ml) was added dropwise methanol(18 ml) at -20° C. The mixture was stirred for 30 min at -20° C. To themixture was added a solution of the residue prepared in referenceexample 7 in methanol at -20° C. After stirred for 1 h at roomtemperature, the mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (3.52 g) having thefollowing physical data.

TLC: Rf 0.22 (n-hexane: ethyl acetate=3:1);

IR (cm⁻¹): ν 3425, 2925, 1713, 1587, 1466, 1439, 1336, 1279, 1159, 1088,1070, 1010, 772, 713.

Reference Example 92-Methoxycarbonylmethyl-5-(tetrahydropyran-2-yl)oxy-1,2,3,4-tetrahydronaphthalene##STR50##

A mixture of the compound prepared in reference example 8 (1.25 g),dihydropyran (0.68 ml), a catalytic amount of pyrdinum p-toluenesulfonicacid and methylene chloride (10 ml) was stirred for 3 days at roomtemperature. After adding of triethylamine (0.5 ml), the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane: ethyl acetate=6:1) to give thetitle compound (1.72 g) having the following physical data.

IR (cm⁻¹): ν 2943, 1738, 1586, 1464, 1438, 1356, 1283, 1251, 1202, 1158,1124, 1076, 1024, 955, 918, 873, 820, 770, 736.

Reference Example 105-(Tetrahydropyran-2-yl)oxy-1,2,3,4-tetrahydronaphthalen-2-yl! aceticacid ##STR51##

To a solution of the compound prepared in reference example 9 (1.72 g)in dimethoxyethane (15 ml) was added 2N aqueous solution of sodiumhydroxide (5.6 ml) at 0° C. This solution was stirred overnight at roomtemperature. After neutralized by addition of 2N hydrochloric acid (5.6ml), the mixture was extracted with ethyl acetate. The extract waswashed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and evaporated.The residue was recrystallized from n-hexane--ethyl acetate to give thetitle compound (1.27 g) having the following physical data.

mp.: 104˜109° C.;

MS (m/z): 290 (M⁺), 256, 234.

Reference Example 112-Diphenylmethylcarbonylmethoxycarbonylmethyl-5-(tetrahydropyran-2-yl)oxy-1,2,3,4-tetrahydronaphthalene##STR52##

To a solution of the compound prepared in reference example 10 (290 mg)in ethanol (2 ml) was added 1N aqueous solution of sodium hydroxide (1ml). The solution was concentrated under reduced pressure to give sodiumsalt of the compound prepared in reference example 10. A mixture ofsodium salt thus obtained, tetra-n-butylammonium bromide (32 mg) and3-bromo-1,1-diphenyl-2-propanone (578 mg) in toluene (5.0 ml) wasstirred overnight at room temperature. The mixture was poured intowater, and was extracted with ether. The extract was washed with waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=5:1) to give the title compound (447 mg) having the followingphysical data.

TLC: Rf 0.45 (n-hexane: ethyl acetate=3:1);

IR (cm⁻¹): ν 3029, 2938, 1735, 1585, 1499, 1464, 1412, 1358, 1251, 1202,1155, 1123, 1078, 1024, 955, 918, 900, 873, 820, 771, 747, 703.

Reference Example 12 2-(4-Diphenylmethyloxazol-2-yl)methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene ##STR53##

A mixture of the compound prepared in reference example 11 (386 mg),ammonium acetate (298 mg) and acetic acid (2.0 ml) was refluxed for 2.5h. The mixture was diluted with ether. The mixture was washed with anaqueous solution of potassium carbonate, water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (ethyl acetate: n-hexane=1:4) to give thetitle compound (147 mg) having the following physical data.

TLC: Rf 0.45 (ethyl acetate: n-hexane=1:2);

IR (cm⁻¹): ν 3061, 3028, 2924, 2362, 1736, 1587, 1571, 1495, 1465, 1453,1435, 1338, 1307, 1247, 1202, 1156, 1123, 1099, 1032, 995, 956, 904,836, 770, 749, 701, 507.

Reference Example 13(5-tert-butylcarbonyloxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid##STR54##

To a mixture of the compound prepared in reference example 7 (600 mg),2N aqueous solution of sodium hydroxide (2.91 ml) and dioxane (3.0 ml)was added pivaloyl chloride (0.39 ml) at 0° C. The mixture was stirredfor 3 h at room temperature. After quenched by addition of 2Nhydrochloric acid, the mixture was extracted with ethyl acetate. Theextract was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (chloroform: methanol=19:1)to give the title compound (408 mg) having the following physical data.

TLC: Rf 0.43 (methanol: chloroform=1:9);

IR (cm⁻¹): ν 2975, 2932, 1751, 1708, 1582, 1482, 1461, 1413, 1368, 1282,1236, 1125, 1032, 941, 767, 712.

Reference Example 142-Bromomethylcarbonylmethyl-5-tert-butylcarbonyloxy-1,2,3,4-tetrahydronaphthalene##STR55##

To a mixture of the compound prepared in reference example 13 (390 mg)and trace amount of DMF was added oxalyl chloride (4.0 ml) at roomtemperature. The mixture was stirred for 1.5 h at room temperature. Themixture was concentrated under reduced pressure to remove excess oxalylchloride and the residue was diluted with ether. This solution was addedto an ethereal solution of diazomethane (20 ml) at 0° C. and the mixturewas stirred for 2 h at 0° C. Gaseous hydrogen bromide (prepared fromtetralin and bromine) was bubbled into the mixture for a period of 20min at 0° C. After adding of water, the organic layer was separated. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfate,and evaporated to give the title compound (424 mg) having the followingphysical data.

TLC: Rf 0.22 (n-hexane: ethyl acetate=7:1);

IR (cm⁻¹): ν 2974, 2932, 1747, 1581, 1479, 1460, 1397, 1364, 1280, 1236,1127, 1032, 983, 898, 768, 711.

Reference Example 152-Diphenyimethylcarbonyloxymethylcarbonylmethyl-5-tert-butylcarbonyloxy-1,2,3,4-tetrahydronaphthalene##STR56##

A mixture of sodium diphenylacetate (1.67 mmol), tetra-n-butylammoniumbromide (32 mg), the compound prepared in reference example 14 (400 mg)and toluene (5.0 ml) was stirred overnight at room temperature. Themixture was poured into water and the mixture was extracted with ether.The extract was washed with water and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfate,and evaporated. The residue was purified by silica gel columnchromatography (n-hexane: ethyl acetate=5:1) to give the title compound(531 mg) having the following physical data.

TLC: Rf 0.40 (n-hexane: ethyl acetate:=3:1);

IR (cm⁻¹): ν 3029, 2974, 2931, 1747, 1581, 1496, 1460, 1397, 1370, 1279,1235, 1186, 1126, 899, 767, 746, 702.

Reference Example 162-(2-Diphenylmethyloxazol-4-yl)methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene##STR57##

To a solution of the compound (190 mg) obtained by the same procedure asreference example 12, using the compound prepared in reference example15, in dimethoxyethane (3.0 ml) and methanol (0.5 ml) was added 1Naqueous solution of sodium hydroxide (1.5 ml) at 0° C. The solution wasstirred for 2 h at room temperature. After neutralized by addition of 1Nhydrochloric acid (1.5 ml), the mixture was extracted with ether. Theextract was washed with a saturated aqueous solution of sodiumbicarbonate and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and evaporated.The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (150 mg) having thefollowing physical data.

TLC: Rf 0.25 (n-hexane: ethyl acetate:=3:1);

IR (cm⁻¹): ν 3062, 3029, 2921, 2844, 1735, 1587, 1557, 1495, 1464, 1338,1275, 1202, 1158, 1091, 1032, 1004, 985, 846, 770, 751, 699, 640, 585,506.

Reference Example 17 Methyl2-(2-hydroxyimino-n-pentyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR58##

A mixture of methyl2-(2-oxo-n-pentyl)-1,2,3,4-tetrahydronaphthalen-2-yloxy! acetate (608mg), hydroxyamine hydrochloride (290 mg), triethylamine (0.55 ml) andethanol (5.0 ml) was stirred overnight at room temperature. After addingof triethylamine (1.0 ml), the mixture was concentrated under reducedpressure. The residue was dissolved into a mixture of ether and water.The organic layer was separated and was washed with water and asaturated aqueous solution of sodium chloride, successively, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica gel column chromatography (n-hexane: ethyl acetate=2:1) to givethe title compound (540 mg) having the following physical data.

mp.: 95.9˜97° C.;

TLC: Rf 0.24 (n-hexane: ethyl acetate:=3:1);

IR (cm⁻¹): ν 3246, 2942, 1767, 1586,1468, 1436, 1347, 1311, 1276, 1200,1195, 1127, 1003, 963, 948, 828, 766, 744, 709.

Reference Example 18 Methyl2-(3-bromo-2-oxopropyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetate##STR59##

By the same procedure as reference example 14, using(5-methoxycarbonylmethyl-1,2,3,4-tetrahydronaphthalene-2-yl) aceticacid, the title compound having the following physical data was given.

mp.: 77˜78° C.;

TLC: Rf 0.25 (n-hexane: ethyl acetate:=4:1);

IR(cm⁻¹): ν 3010, 2944, 2920, 2905, 1763, 1735, 1583, 1469, 1435, 1398,1384, 1343, 1264, 1218, 1205, 1149, 1101, 1088, 1030, 966, 777, 745,710, 608.

Reference Example 19

A mixture of amidinodiphenylmethane (A) andamidinodiphenylhydroxymethane (B) ##STR60##

A mixture of diphenylacetonitrile (10 g) and ammonium thioisocyanate (16g) was stirred for 5 h at 180° C. The mixture was cooled and quenched byaddition of hot water. The mixture was filtrated and to the filtrate wasadded 5N aqueous solution of sodium hydroxide. The mixture was extractedwith chloroform. The extract was dried over anhydrous sodium sulfate,and evaporated. The residue was treated with picric acid (1.5 g) andethanol (50 ml). The precipitate was filtrated, washed with ethanol anddissolved in aqueous solution of sodium hydroxide. This solution wasextracted with chloroform. The extract was dried over anhydrous sodiumsulfate, and evaporated to give a mixture of title compounds having thefollowing physical data.

TLC: (A) Rf 0.45, (B) Rf 0.38 (chloroform: methanol: aceticacid=17:2:1);

NMR: δ7.46-7.17 (10H, m), 4.94 (1H, s).

Reference Example 20 Methyl2-(4-benzoylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR61##

By the same procedure as a series of reactions of reference example 1→example 1, using 4-benzoylpyrazole instead of the compound prepared inreference example 4, the title compound having the following physicaldata was given.

TLC: Rf 0.43 (n-hexane: ethyl acetate:=1:1).

Reference Example 21 Methyl1-(2-cyanoethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetate ##STR62##

A mixture of potassium cyanide (1.16 g) and 18-Crown-6 (registered trademark, 236 mg) in acetonitrile (18 ml) was stirred for 15 min under anatmosphere of argon. To the mixture was added a solution of methyl1-(2-bromoethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetate (2.92 g)and tributylphosphine (1.99 g) in acetonitrile (10 ml). To the mixturewas added dropwise a solution of carbon tetrachloride (0.95 ml) inacetonitrile (10 ml) under cooling with ice. The mixture was stirredovernight at room temperature. The mixture was diluted with ether, andthe mixture was washed with 10% aqueous solution of citric acid. To thissolution was added carbon tetrachloride (10 ml), and washed with waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=1:9) to give the title compound (1.72 g) having the followingphysical data.

NMR: δ7.05 (1H, t, J=8 Hz), 6.83 (1H, d, J=8 Hz), 6.52 (1H, d, J=8Hz),2.90-2.60 (5H, m), 2.30-1.50 (6H, m).

Reference Example 22 Methyl1-(3-amino-3-hydroxyimino)propyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR63##

To a mixture of ethanol and water (5:1, 30 ml) were successively addedthe compound prepared in reference example 21 (1.01 g), hydroxyaminehydrochloride (331 mg) and sodium acetate (391 mg). The mixture wasrefluxed overnight. The mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give the title compound (132 mg) havingthe following physical data.

MS (m/z): 306 (M⁺ +1).

Reference Example 23 Methyl 1-3-(diphenylmethylcarbonyloxyimino)-3-aminopropyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR64##

A suspension of diphenylacetic acid (201 mg) and thionyl chloride (5 ml)was refluxed for 1 h. The mixture was cooled to room temperature, andconcentrated under reduced pressure. To a solution of the residue andthe compound prepared in reference example 22 (132 mg) in methylenechloride (5 ml) was added triethylamine (0.27 ml). The mixture wasstirred overnight at room temperature. After quenched by addition ofwater, the mixture was extracted with ether. The extract was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=1:1) to give the title compound (67 mg) having the followingphysical data.

MS (m/z): 501 (M⁺ +1).

Reference Example 242-(N-Methoxy-N-methylcarbamoylmethyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR65##

To a solution of 2-carboxymethyl-5-methoxy-1 2,3,4-tetrahydronaphthalene(10.1 g) in methylene chloride (20 ml) was added oxalyl chloride (30 ml)at 0° C. The mixture was stirred for 45 min at room temperature. Themixture was concentrated under reduced pressure, and the residue wasdissolved into methylene chloride (50 ml). This solution was added to asolution of N, O-dimethyhydroxylamine hydrochloride (5.37 g),triethylamine (19.2 ml) and methylene chloride (150 ml) at 0° C. Themixture was stirred for 30 min at room temperature. After adding of 1Nhydrochloric acid, the mixture was extracted with ethyl acetate. Theextract was washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=2:1) to give the title compound (10.88 g)having the following physical data.

MS(m/z): 263 (M⁺).

Reference Example 252-(5-Hydroxy-5,5-diphenyl-2-oxo-3-pentynyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR66##

To a solution of 1,1-diphenyl-2-propyn-1-ol (2.15 g) in THF (20 ml)added dropwise n-butyllithium (13 ml, 1.6 M/L in hexane solution) at-70° C. The mixture was stirred for 30 min at the same temperature. Tothe mixture was added boron trifluoride etherate (2.7 ml), and stirredfor 30 min. To the mixture was added a solution of the compound preparedin reference example 24 (900 mg) in THF (10 ml) at -70° C., and stirredfor 1 h. After quenched by addition of ammonium chloride, the mixturewas extracted with ethyl acetate. The extract was washed with water anda saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=7:1) to give the title compound (1.05 g) having the followingphysical data.

MS (m/z): 410 (M⁺).

Reference Example 26 2-5-(1,1-Diphenyl-1-hydroxymethyl)isoxazol-3-yl)methyl-5-methyoxy-1,2,3,4-tetrahydronaphthalene##STR67##

A mixture of the compound prepared in reference example 25 (820 mg),hydroxyamine hydrochloride (1.50 g), pyridine (10 ml) and ethanol (10ml) was stirred for 6 h at 100° C. After cooled to room temperature, themixture was concentrated under reduced pressure to remove the solvent.To the residue was added water, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=9:1) to give the title compound (680 mg) havingthe following physical data.

MS (m/z): 425 (M⁺).

Reference Example 272-(5-Diphenylmethylisoxazol-3-yl)methyl-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR68##

To a mixture of the compound prepared in reference example 26 (650 mg)and trifluoroacetic acid (6 ml) was added a solution of triethylsilane(350 mg) in methylene chloride (2 ml) at 0° C. The mixture was stirredfor 1 h at room temperature. The mixture was concentrated under reducedpressure to remove the solvent. To the residue was added a saturatedaqueous solution of sodium bicarbonate, and extracted with ethylacetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (n-hexane: ethyl acetate=9:1) to give thetitle compound (525 mg) having the following physical data.

MS (m/z): 409 (M⁺).

Reference Example 282-(5-Diphenylmethylisoxazol-3-yl)methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene##STR69##

To a solution of the compound prepared in reference example 27 (470 mg)in methylene chloride (6 ml) was added boron tribromide (0.34 ml) at 0°C. The mixture was stirred for 2 h at the same temperature. The mixturewas poured into ice water, and the mixture was extracted with ethylacetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (n-hexane: ethyl acetate=5:1) to give thetitle compound (328 mg) having the following physical data.

MS (m/z): 395 (M⁺).

Reference Example 292-(3,3-Dibromo-2-propenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR70##

To a solution of carbon tetrabromide (19.5 g) in methylene chloride (50ml) was added triphenylphosphine (30.8 g) at 0° C., and the mixture wasstirred for 10 min. To the mixture was added a solution of2-formylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.09 g; thecompound prepared by method described in the specification of theJapanese Patent Application No. 3-130467) in methylene chloride (25 ml)at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture wasgradually added n-hexane, and filtrated to removetriphenylphosphineoxide. The filtrate was washed with water and asaturated aqueous solution of sodium chloride, successively, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica gel column chromatography (n-hexane: ethyl acetate=24:1) to givethe title compound (6.42 g) having the following physical data.

MS (m/z): 362,360,358 (M⁺).

Reference Example 302-(2-Propynyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene ##STR71##

To a solution of the compound prepared in reference example 29 (6.20 g)in THF (70 ml) was added dropwise n-butyllithium (23.7 ml; 1.6 M/L inhexane solution) at -70° C. The mixture was stirred for 30 min at -70°C. After quenched by addition of water and aqueous solution of ammoniumchloride at the same temperature, the mixture was warmed up to roomtemperature. The mixture was extracted with hexane--ethyl acetate (6:1).The extract was washed with water and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfate,and evaporated. The residue was purified by silica gel columnchromatography (n-hexane: ethyl acetate=24:1) to give the title compound(3.40 g) having the following physical data.

MS (m/z): 200 (M⁺).

Reference Example 312-(5,5-Diphenyl-4-oxo-2-pentynyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR72##

To a mixture of ethylmagnesium bromide (5.7 ml; 3.0 M/L in ethersolution) and THF (40 ml) was added dropwise a solution of the compoundprepared in reference example 30 (3.0 g) in THF (20 ml) over a 10 minperiod. The mixture was stirred for 2 h at room temperature. To themixture was added a solution of diphenylacetaldehyde (2.94 g) in THF (10ml). The mixture was stirred for 2 h. After quenched by addition ofammonium chloride, the mixture was extracted with ether. The extract waswashed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and evaporated. Toa solution of the residue in ether (50 ml) was added manganese (IV)oxide (2.7 g) at room temperature. The mixture was stirred for 2 h. Themixture was filtrated, and evaporated. The residue was purified bysilica gel column chromatography (n-hexane: ethyl acetate=7:1) to givethe title compound (2.41 g) having the following physical data.

MS (m/z): 394 (M⁺).

Reference Example 322-(3-Diphenylmethylisoxazol-5-yl)methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene##STR73##

By the same procedure as a series of reactions of reference example26→reference example 28, using the compound prepared in referenceexample 31, the title compound having the following physical data wasgiven.

MS (m/z): 395 (M⁺).

Reference Example 332-(4-lmino-2-hydroxy-5,5-diphenyl-2-pentenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR74##

A mixture of the compound (600 mg) prepared by the same procedure asreference example 26, using the compound prepared in reference example31, Raney nickel (300 mg; registered trade mark) and ethanol (5 ml) wasstirred overnight under an atmosphere of hydrogen. The mixture wasfiltered through Celite (registered trade mark), and evaporated. Theresidue was purified by silica gel column chromatography (ethyl acetate:benzene=7:93) to give the title compound (325 mg) having the followingphysical data.

MS (m/z): 411 (M⁺).

Reference Example 342-(3-Diphenylmethylisothiazol-5-yl)methyl-5-methoxy-1,2,3,4-tetrahydronaphthalene##STR75##

A mixture of the compound prepared in reference example 33 (255 mg),p-chloranil (153 mg), phosphorus pentasulfide (413 mg) and toluene (4ml) was refluxed for 30 min. After cooled to room temperature, to themixture was added benzene. The mixture was filtrated, and evaporated.The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (128 mg) having thefollowing physical data.

MS (m/z): 425 (M⁺).

Reference Example 352-(3-Diphenylmethylisothiazol-5-yl)methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene##STR76##

By the same procedure as reference example 7, using the compoundprepared in reference example 34, the title compound (90 mg) having thefollowing physical data was given.

MS (m/z): 411 (M⁺).

Example 1 Methyl2-(4-diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR77##

To a suspension of sodium hydride (60% containing, 68 mg) in DMF (2.0ml) was added a solution of the compound prepared in reference example 4(190 mg) in DMF (2.0 ml) with stirring at room temperature. Afterstirred for 30 min at room temperature, to the mixture was added asolution of the compound prepared in reference example 1 (280 mg) in DMF(2.0 ml). After stirred for 30 min, the mixture was quenched by additionof 1N hydrochloric acid. The mixture was extracted with ethyl acetate -n-hexane (1:2). The extract was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=5:2) to give the title compound (90 mg) havingthe following physical data.

TLC: Rf 0.36 (n-hexane: ethyl acetate:=2:1);

IR (cm⁻¹): ν 3061, 3027, 2928, 1762, 1741, 1602, 1586, 1494, 1466, 1374,1346, 1207, 1120, 1031, 1018, 992, 918, 849, 764, 702.

Example 22-(4-Diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!aceticacid ##STR78##

The compound prepared in example 1 (78 mg) was dissolved into THF (2.0ml) and methanol (2.0 ml). 1N aqueous solution of sodium hydroxide (0.5ml) was added to the solution with stirring at room temperature. Thissolution was stirred for 1 h at room temperature. After neutralized byaddition of 2N hydrochloric acid (0.25 ml), the mixture was extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andevaporated. The residue was recrystallized from n-hexane--ethyl acetateto give the title compound (62 mg) having the following physical data.

TLC: Rf 0.31 (chloroform:methanol=17:3);

NMR: δ7.37-7.14 (1H, m), 7.02 (1H, t, J=8.0 Hz), 6.98 (1H, s), 6.67 (1H,d, J=8.0 Hz), 6.56 (1H, d, J=8.0 Hz), 5.35 (1H, s), 4.62 (2H,s) 4.50(1H, brs), 4.15-3.93 (2H, m), 3.05-2.85 (1H, m), 2.71-2.10 (4H, m),1.93-1.75 (1H, m), 1.45-1.20 (1H, m).

Example 2(a)-2(l)

By the same procedure as example 2, the compounds shown in the followingtable 3 were given by using the compound obtained from the sameprocedure as example 1 (provided that the compounds shown as (a) in thefollowing table 3 were used instead of the compound prepared inreference example 4).

                                      TABLE 3    __________________________________________________________________________    EX.    No.       Structure of the compound (a)                        Structure of the example compound                                                  TLC   IR (cm.sup.-1)    __________________________________________________________________________    2(a)       1 #STR79##                        3 #STR80##                Rf 0.09 (chloroform:                                                  methanol =                                                        ν 2914, 2487,                                                        1736,  .sup. 1585,                                                        1507, 1467,  .sup.                                                        1434, 1229, 1117,                                                        .sup. 767, 695.    2(b)       2 #STR81##                        4 #STR82##                Rf 0.21 (chloroform:                                                  methanol =                                                        ν 2918, 1741,                                                        1598,  .sup. 1585,                                                        1498, 1464,  .sup.                                                        1378, 1281, 1210,                                                        .sup. 1121, 765,                                                        695.    2(c)       5 #STR83##                        7 #STR84##                Rf 0.09 (chloroform:                                                  methanol =                                                        ν 3060, 2921,                                                        1733,  .sup. 1585,                                                        1511, 1466,  .sup.                                                        1237, 1111, 1078,                                                        .sup. 705, 696.    2(d)       6 #STR85##                        8 #STR86##                Rf 0.18 (chloroform:                                                  methanol =                                                        ν 2926, 1751,                                                        1599,  .sup. 1583,                                                        1548, 1504,  .sup.                                                        1462, 1435, 1364,                                                        .sup. 1209, 763,                                                        707.    2(e)       9 #STR87##                        1 #STR88##                Rf 0.18 (chloroform:                                                  methanol =                                                        ν 2931, 1764,                                                        1666,  .sup. 1585,                                                        1498, 1466,  .sup.                                                        1440, 1402, 1271,                                                        .sup. 1202, 1125,                                                        761,  .sup. 712,                                                        676.    2(f)       0 #STR89##                        2 #STR90##                Rf 0.18 (chloroform:                                                  methanol =                                                        ν 2924, 1739,                                                        1688,  .sup. 1506,                                                        1489, 1468,  .sup.                                                        1409, 1210, 1123,                                                        .sup. 1048, 749,                                                        700.    2(g)       3 #STR91##                        5 #STR92##                Rf 0.28 (chloroform:                                                  methanol: acetic acid =                                                  17:2:1)                                                        ν 3449, 3060,                                                        3028,  .sup. 2479,                                                        1732, 1586,  .sup.                                                        1495, 1466, 1454,                                                        .sup. 1309, 1220,                                                        1156,  .sup. 1109,                                                        1083, 1032,  .sup.                                                        832, 758, 703,  .sup.                                                        637.    2(h)       4 #STR93##                        6 #STR94##                Rf 0.29 (chloroform:                                                  methanol =                                                        (film method) ν                                                        3060, 3026, 2928,                                                        .sup. 1762, 1741,                                                        1602,  .sup. 1585,                                                        1515, 1494,  .sup.                                                        1466, 1451, 1414,                                                        .sup. 1376, 1345,                                                        1207,  .sup. 1120,                                                        1052, 1032,  .sup.                                                        1003, 962, 847,                                                        .sup. 761, 702.    2(i)       7 #STR95##                        9 #STR96##                Rf 0.25 (methylene                                                  chloride: methanol =                                                        δ 8.43(2H, m),                                                        7.70   (1H, m),                                                        7.50-7.10   (8H, m),                                                        6.98   (1H, t,                                                        J=8Hz), 6.70-                                                        6.50(2H, m), 5.53                                                        (1H, s), 4.57(2H, s),                                                          4.08(2H, d, J=7Hz),                                                          2.95(1H, m), 2.80-                                                         2.10(4H, m), 1.86                                                        (1H, m), 1.38(1H,                                                        m).    2(j)       8 #STR97##                        0 #STR98##                Rf 0.22 (chloroform:                                                  methanol =                                                        δ 7.40-7.00(12H,                                                         m),   6.80(1H, brs),                                                          6.78(1H, d, J=8Hz),                                                          6.60(1H, d, J=8Hz),                                                          5.59(1H, s),                                                        4.63(2H, s),                                                        4.38(2H, m),                                                        3.08-2.92(1H, m),                                                        2.75-2.13(4H, m),                                                        1.95-1.77(1H, m),                                                        1.42-1.21(1H, m).    2(k)       1 #STR99##                        3 #STR100##               Rf 0.18 (chloroform:                                                  methanol =                                                        δ 7.39-7.01(12H,                                                         m),   6.85(1H, brs),                                                          6.76(1H, d, J=8Hz),                                                          6.58(1H, d, J=8Hz),                                                          5.64(1H, s), 4.56                                                        (2H, s), 4.24(2H, m),                                                          3.05-2.85(1H, m),                                                        2.73-2.12(4H, m),                                                        1.94-1.76(1H, m),                                                        1.41-1.12 (1H, m).    2(l)       2 #STR101##                        4 #STR102##               Rf 0.16 (chloroform:                                                  methanol =                                                        δ 7.41-6.99(13H,                                                         m),   6.78(1H, d,                                                        J=8Hz),   6.63(1H, d,                                                        J=8Hz),   5.26(1H,                                                        s), 4.62   (2H, s),                                                        4.03(2H, m),                                                        3.03-2.84(1H, m),                                                        2.73-2.13(4H, m),                                                        1.95-1.76(1H, m),                                                        1.43-1.20(1H,    __________________________________________________________________________                                                        m).

The example compounds shown in the table 3 are named as follows:

2(a)2-(4,5-Diphenylimidazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(b)2-(1,4,5-Triphenylimidazol-2-ylthio)methy-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(c)2-(4,5-Diphenylimidazol-2-ylthio)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(d)2-(1,4,5-Triphenylimidazol-2-yloxy)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(e)2-(3,4,5-Triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(f)2-(3-Phenyl-2-oxo-2,3-dihydrobenzimidazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(g)2-(4-Diphenylmethylimidazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(h)2-(3-Diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(i)2-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(j)2-(4-Diphenylmethyl-1,2,3-triazol-2-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(k)2-(4-Diphenylmethyl-1,2,3-triazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

2(l)2-(4-Diphenylmethyl-1,2,3-triazol-3-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

Example 3 Methyl 2-2-(4,5-diphenylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR103##

By the same procedure as example 1 (provided that 4,5-diphenylmidazolewas used instead of the compound prepared in reference example 4), thetitle compound having the following physical data was given by using thecompound obtained from the same procedure as reference example 1, usingmethyl 2-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetateinstead of methyl (2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate.

NMR: δ7.64 (1H, s), 7.60-7.10 (10H, m), 7.02 (1H, t, J=7 Hz), 6.62 (1H,d, J=7 Hz), 6.48 (1H, d, J=7 Hz), 4.62 (2H, s), 3.92 (2H, t, J=6 Hz),3.78 (3H, s), 3.00-2.10 (5H, m), 1.95-1.50 (3H, m), 1.25 (1H, m);

IR (cm⁻¹): ν 3434, 2925, 1761, 1603, 1585, 1507, 1466, 1441, 1373, 1245,1207, 1118, 1022, 954, 918, 773, 721, 700, 654.

Example 4 2-2-(4,5-Diphenylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR104##

By the same procedure as example 2, by using the compound prepared inexample 3, the title compound having the following physical data wasgiven.

mp.: 197° C.;

TLC: Rf 0.16 (methylene chloride: methanol =9:1);

IR (cm³¹ 1): ν 3453, 2922, 1734, 1585, 1551, 1467, 1441, 1244, 1113,767, 697.

Example 4(a)˜4(f)

By the same procedure as example 2, the compounds shown in the followingtable 4 were given by using the compound obtained from the sameprocedure as example 3, using the compound shown as (a) in the followingtable 4 instead of 4,5-diphenylimidazole.

                                      TABLE 4    __________________________________________________________________________    EX. No.        Structure of the compound (a)                       Structure of the example compound                                                    TLC   IR    __________________________________________________________________________                                                          (cm.sup.-1)    4(a)        5 #STR105##                       7 #STR106##                  Rf 0.22 (methylene                                                    chloride: methanol =                                                          ν 3449, 2918,                                                          1732,  .sup. 1582,                                                          1495, 1465,  .sup.                                                          1423, 1200, 1117,                                                          .sup. 764, 702,                                                          693.    4(b)        6 #STR107##                       8 #STR108##                  Rf 0.16 (methylene                                                    chloride: methanol =                                                          ν 2923, 1897,                                                          1735,  .sup. 1585,                                                          1466, 1236,  .sup.                                                          1111, 765, 695.    4(c)        9 #STR109##                       1 #STR110##                  Rf 0.32 (methylene                                                    chloride: methanol =                                                          ν 2925, 1736,                                                          1583,  .sup. 1544,                                                          1501, 1465,  .sup.                                                          1390, 1335, 1203,                                                          .sup. 1118, 764,                                                          705.    4(d)        0 #STR111##                       2 #STR112##                  Rf 0.32 (methylene                                                    chloride: methanol =                                                          ν 2928, 1724,                                                          1696,  .sup. 1653,                                                          1585, 1500,  .sup.                                                          1455, 1406, 1382,                                                          .sup. 1230, 1113,                                                          756,  .sup. 696.    4(e)        3 #STR113##                       5 #STR114##                  Rf 0.32 (methylene                                                    chloride: methanol =                                                          ν 2911, 1753,                                                          1675,  .sup. 1587,                                                          1506, 1489,  .sup.                                                          1415, 1268, 1213,                                                          .sup. 1126, 761,                                                          744,  .sup. 730,                                                          695.    4(f)        4 #STR115##                       6 #STR116##                   Rf 0.32 (chloroform:                                                    methanol =                                                           ν 3027, 2914,                                                          2531,  .sup. 1746,                                                          1601, 1584,  .sup.                                                          1495, 1466, 1431,                                                          .sup. 1350, 1313,                                                          1265,  .sup. 1218,                                                          1121, 1014,  .sup.                                                          761, 728, 705,                                                          .sup. 678.    __________________________________________________________________________

The example compounds shown in the table 4 are named as follows:

4(a)2-(2-(1,4,5-Triphenylimidazol-2-ylthio)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

4(b)2-(2-(4,5-Diphenylimidazol-2-ylthio)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

4(c)2-(2-(1,4,5-Triphenylimidazol-2-yloxy)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

4(d)2-(2-(3,4,5-Triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

4(e)2-(2-(3-Phenyl2-oxo-2,3-dihydrobenzimidazol-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

4(f)2-(2-(4-Diphenylmethylpyrazol-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

Example 5

Methyl 1-2-(4,5-diphenylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR117##

By the same procedure as example 3, by using methyl1-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetate insteadof methyl 2-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate, the title compound having the following physical data wasgiven.

IR (cm⁻¹): ν 3066, 2932, 2861, 2361, 1761, 1676, 1603, 1581, 1506, 1463,1442, 1371, 1339, 1244, 1210, 1121, 1073, 1022, 954, 918, 849, 775, 755,721, 699;

MS (m/z): 466 (M+).

Example 6 1-2-(4,5-Diphenylimidazol-1-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR118##

By the same procedure as example 2, by using the compound prepared inexample 5, the title compound having the following physical data wasgiven.

TLC: Rf 0.17 (methylene chloride:methanol=10:1);

IR (cm⁻¹): ν 3449, 3058, 2932, 2862, 1736, 1603, 1581, 1508, 1463, 1444,1339, 1230, 1115, 1075, 920, 885, 775, 722, 700.

Example 6(a)˜6(d)

By the same procedure as example 2, the compounds shown in the followingtable 5 were given by using the compound obtained from the sameprocedure as example 3, and that shown as (a) in the following table 5instead of 4,5-diphenylimidazole.

                                      TABLE 5    __________________________________________________________________________    EX. No.         Structure of the compound (a)                         Structure of the example compound                                                   TLC   IR    __________________________________________________________________________                                                         (cm.sup.-1)    6(a)         7 #STR119##                         9 #STR120##               Rf 0.11 (methylene                                                   chloride: methanol =                                                         ν 3061, 2928,                                                         2859,  .sup. 1898,                                                         1736, 1582,  .sup.                                                         1510, 1491, 1464,                                                         .sup. 1407, 1373,                                                         1340,  .sup. 1306,                                                         1234, 1180,  .sup.                                                         1111, 1073, 1046,                                                         .sup. 1027, 917,                                                         883,  .sup. 766,                                                         696, 588,  .sup.                                                         537.    6(b)         8 #STR121##                         0 #STR122##               Rf 0.18 (methylene                                                   chloride: methanol =                                                         ν 3059, 2931,                                                         2863,  .sup. 1737,                                                         1695, 1656,  .sup.                                                         1597, 1583, 1499,                                                         .sup. 1450, 1402,                                                         1373,  .sup. 1313,                                                         1224, 1176,  .sup.                                                         1117, 1074, 1027,                                                         .sup. 919, 886, 802,                                                          .sup. 760, 712,                                                         699,  .sup. 657,                                                         515.    6(c)         1 #STR123##                         3 #STR124##               Rf 0.29 (chloroform:                                                   methanol =                                                         ν 3027, 2932,                                                         1736,  .sup. 1582,                                                         1494, 1464,  .sup.                                                         1373, 1217, 1118,                                                         .sup. 1079, 1015,                                                         875,  .sup. 776,                                                         752, 702.    6(d)         2 #STR125##                         4 #STR126##               Rf 0.28 (chloroform:                                                   methanol =                                                         ν 2932, 1735,                                                         1464,  .sup. 1222,                                                         1116,    __________________________________________________________________________                                                         703.

The example compounds shown in the table 5 are named as follows:

6(a)1-(2-(4,5-Diphenylimidazol-2-ylthio)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

6(b)1-(2-(1,4,5-Triphenyl-2-oxo-2,3-dihydroimidazol-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

6(c)1-(2-(4-Diphenylmethylpyrazol-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

6(d)1-(2-(4-((3-Pyridyl)phenylmethy)pyrazol-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

Example 7 Methyl 1-2-(3-diphenylmethyl-1,2,4-oxadiazol-5-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR127##

A suspension of the compound prepared in reference example 6 (400 mg) intoluene (20 ml) was stirred overnight. The mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1) to give the title compound(305 mg) having the following physical data.

MS (m/z): 482 (M⁺), 423, 315, 273, 263, 250, 167;

IR (cm⁻¹): ν 3029, 2935, 1762, 1739, 1581, 1496, 1464, 1374, 1210, 1121,1080, 1033, 846, 777, 702.

Example 8 1-2-(3-Diphenylmethyl-1,2,4-oxadiazol-5-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxyl!acetic acid ##STR128##

By the same procedure as example 2, by using the compound prepared inexample 7, the title compound having the following physical data wasgiven.

TLC: Rf 0.11 (methanol:methylene chloride=1:9);

IR (cm⁻¹): ν 2935, 1748, 1708, 1578, 1496, 1465, 1429, 1377, 1240, 1123,1032, 923, 782, 747, 722, 702, 634, 587.

Example 8(a) and (b)

By the same procedure as a series of reaction of example 7→example 8,the compounds shown in the following table 6 were given by using methyl!2-((1-amino-2,2-diphenylethylidene)aminoxycarbonylmethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate or the compound prepared in reference example 23 instead of thecompound prepared in reference example 6.

                                      TABLE 6    __________________________________________________________________________    EX. No.         Structure of the example compound                                    NMR    __________________________________________________________________________    8(a)         5 #STR129##                δ 7.40-7.20(10H, m),   7.06(1H, t,                                    J=8Hz),   6.72(1H, d, J=8Hz),   6.53(1H,                                    d, J=8Hz),   5.60(1H, s), 4.65(2H, s),                                    3.10-1.80(8H, m),   1.50(1H, m).    8(b)         6 #STR130##                δ 7.40-7.10(10H, m),   7.05(1H, t,                                    J=8Hz),   6.85(1H, d, J=8Hz),   6.53(1H,                                    d, J=8Hz),   5.72(1H, s), 4.62(2H, s),                                    2.90-1.60(11H, m).    __________________________________________________________________________

The example compounds shown in the table 6 are named as follows:

8(a)2-(3-Diphenylmethyl-1,2,4-oxadiazol-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

8(b)1-(2-(5-Diphenylmethy-1,2,4-oxadiazol-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

Example 9 Methyl2-(4-diphenylmethyloxazol-2-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR131##

To a suspension of the compound prepared in reference example 12 (132mg) and potassium carbonate (93 mg) in acetone (2.0 ml) was stirringadded methyl bromoacetate (0.063 ml) with stirring at room temperature.The mixture was stirred for 4 h at 40° C. After cooled to roomtemperature, the mixture was filtrated, and evaporated. The residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=1:4) to give the title compound (145 mg) having thefollowing physical data.

TLC: Rf 0.28 (ethyl acetate:n-hexane=1:3);

IR (cm⁻¹): ν 3027, 2925, 1762, 1585, 1495, 1466, 1452, 1437, 1345, 1282,1207, 1156, 1120, 1099, 1032, 997, 839, 767, 750, 702.

Example 102-(4-Diphenylmethyloxazol-2-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR132##

By the same procedure as example 2, by using the compound prepared inexample 9, the title compound having the following physical data wasgiven.

mp.: 129.5˜131.5° C.;

TLC: Rf 0.24 (methanol:chloroform=3:17);

IR (cm⁻¹): ν 3029, 2923, 1748, 1585, 1570, 1495, 1467, 1453, 1433, 1307,1243, 1212, 1120, 1032, 984, 913, 764, 730, 700.

Example 11 Methyl2-(2-Diphenylmethyloxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR133##

By the same procedure as example 9, by using the compound prepared inexample 16, the title compound having the following physical data wasgiven.

mp.: 91˜93° C.;

TLC: Rf 0.32 (n-hexane:ethyl acetate=3:1);

IR (cm⁻¹): ν 3100, 3028, 2933, 1756, 1601, 1585, 1566, 1495, 1463, 1378,1345, 1275, 1202, 1168, 1117, 1086, 1031, 987, 955, 770, 757, 742, 718,701, 538.

Example 122-(2-Diphenylmethyloxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR134##

By the same procedure as example 2, by using the compound prepared inexample 11, the title compound having the following physical data wasgiven.

mp.: 158˜159.5° C.;

TLC: Rf 0.19 (chloroform:methanol=9:1);

IR (cm⁻¹): ν 3414, 3062, 2925, 1756, 1603, 1585, 1557, 1495, 1467, 1451,1435, 1345, 1118, 968, 765, 736, 720, 698, 648, 585.

Example 12(a)2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR135##

By the same procedure as a series of reaction of reference example16→example 11→example 12, the title compound having the followingphysical data was given by using the compound obtained by the sameprocedure as reference example 15 (provided that sodium(3-pyridyl)phenylacetate was used instead of sodium diphenylaceticacid).

NMR: δ8.52-8.30 (2H, m), 7.78-7.64 (1H, m), 7.41-7.15 (7H, m), 7.00 (1H,t, J=8Hz), 6.68 (1H, d, J=8Hz), 6.57 (1H, d, J=8Hz), 5.72 (1H, s), 4.61(2H, s), 3.04-1.90 (8H, m), 1.53-1.33 (1H, m).

Example 13 Methyl2-(2-diphenylmethyl-5-ethyloxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR136##

To diphenylacetyl chloride (6 mmol) was added the compound prepared inreference example 17 under cooling with ice bath. The mixture wasstirred overnight at 100° C. After cooled to room temperature, themixture was poured into water. The mixture was extracted with ethylacetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (first time: n-hexane:ethyl acetate=5:1,second time: benzene:ethyl acetate=97:3) to give the title compound (93mg) having the following physical data.

TLC: Rf 0.29 (benzene:ethyl acetate=19:1);

IR (cm⁻¹): ν 3063, 3029, 2926, 1763, 1603, 1583, 1566, 1455, 1437, 1377,1283, 1206, 1121, 1032, 854, 767, 748, 702.

Example 142-(2-Diphenylmethyl-5-ethyloxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR137##

By the same procedure as example 2, by using the compound prepared inexample 13, the title compound having the following physical data wasgiven.

mp.: 150.5˜151.5° C.;

TLC: Rf 0.27 (chloroform:methanol=9:1);

IR (cm⁻¹): ν 3030, 2974, 2932, 2504, 1907, 1718, 1585, 1562, 1495, 1343,1249, 1211, 1155, 1113, 1032, 767, 747, 727, 701, 633, 586.

Example 15 Methyl2-(2-diphenylmethylimidazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR138##

A mixture of the compound prepared in reference example 18 (350 mg) andthe compound prepared in reference example 19 (450 mg) in chloroform wasrefluxed for 18 h. After cooled to room temperature, the mixture wasquenched by addition of an aqueous solution of sodium bicarbonate. Themixture was extracted with ethyl acetate. The extract was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give the title compound (181 mg) having the followingphysical data.

TLC: Rf 0.23 (ethyl acetate:n-hexane=1:1);

IR (cm⁻¹): ν 3026, 2925, 2362, 1762, 1585, 1495, 1466, 1455, 1438, 1208,1120, 766, 701, 589.

Example 162-(2-Diphenylmethylimidazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR139##

By the same procedure as example 2, the using the compound prepared inexample 15, the title compound having the following physical data wasgiven.

mp.: 170° C.;

TLC: Rf 0.25 (chloroform:methanol:acetic acid=17:2:1);

IR (cm⁻¹): ν 3424, 3030, 2922, 1955, 1641, 1586, 1496, 1411, 1329, 1237,1106, 1081, 1005, 768, 700, 587.

Example 17 Octyl2-(4-diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetate ##STR140##

The compound prepared in example 2 (0.453 g) was dissolved into oxalylchloride (3 ml). The mixture was stirred for 1 h at room temperature.The mixture was concentrated under reduced pressure to remove excessoxalyl chloride. The residue was dissolved into pyridine (2 ml), and tothis solution was added n-octyl alcohol (156 mg). The mixture wasstirred for 1 h at room temperature. The mixture was diluted with ethylacetate. The mixture was washed with water, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=4:1) to give the titlecompound (0.48 g) having the following physical data.

MS (m/z): 565 (M⁺ +1);

TLC: Rf 0.33 (n-hexane:ethyl acetate=3:1).

Example 182-(4-Diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetamide ##STR141##

The compound prepared in example 2 (452 mg) was dissolved into oxalylchloride (2 ml). The mixture was stirred for 1 h at room temperature.The mixture was concentrated under reduced pressure to remove excessoxalyl chloride. The residue was dissolved into methylene chloride (5.0ml). After cooled to 0° C., the mixture was suspended by bubbling thegaseous ammonia into the mixture. After stirred for 30 min at roomtemperature, the precipitate was filtrated off, and the filtrateevaporated. The residue was purified by silica gel column chromatography(methanol:methylene chloride=1:4) to give the title compound (420 mg)having the following physical data.

TLC: Rf 0.22 (methylene chloride:methanol=4:1);

MS (m/z): 451 (M⁺).

Example 19 Amide of2-(4-diphenylmethylpyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid with glycine ##STR142##

A mixture of the carboxylic acid prepared in example 2 (452 mg),glycine-tert-butyl ester hydrochloride (158 mg),2-chloro-1-methylpyridinum iodide (307 mg) and triethylamine (0.42 ml)was dissolved into methylene chloride (5.0 ml). The mixture was stirredfor 4 h at room temperature, and concentrated under reduced pressure.The residue was purified bit silica gel column chromatography (ethylacetate:n-hexane=1:1) to give the condensing compound. To a solution ofthe condensing compound in methylene chloride (3.0 ml) was addedtrifluoroacetic acid (3.0 ml). The mixture was stirred for 3 h at roomtemperature. The mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(methanol:methylene chloride=1:9) to give the title compound (403 mg)having the following physical data.

TLC: Rf 0.21 (methylene chloride:methanol=9:1);

MS (m/z): 509 (M+).

Example 20 1-3-(4-Diphenylmethylpyrazol-1-yl)propyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR143##

By the same procedure as a series of reactions of reference example1→example 1→example 2, by using methyl1-(3-hydroxypropyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy! acetateinstead of methyl (2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate, the title compound having the following physical data wasgiven.

TLC: Rf 0.30 (chloroform:methanol 4:1);

IR (cm⁻¹): ν 3027, 2932, 2862, 1736, 1602, 1582, 1494, 1464,1374, 1340,1216, 1118, 1080, 1015, 874, 752, 702.

Example 21 2-3-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR144##

By the same procedure as a series of reactions of example 1→example 2,the title compound having the following physical data was given by using4-((3-pyridyl)phenylmethyl)pyrazole instead of the compound prepared inreference example 4, and by using the compound obtained by the sameprocedure as reference 1, using methyl2-(3-hydroxy-1-propenyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetateinstead of methyl(2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate.

NMR: δ8.55 (1H, s), 8.43 (1H, d, J=4Hz), 7.62 (1H, d, J=7Hz), 7.37-7.00(10H, m), 6.69 (1H, d, J=8Hz), 6.62 (1H, d, J=8Hz), 6.32-6.21 (2H, m),5.40 (1H, s), 4.88 (2H, d, J=6Hz), 4.59 (1H, s), 3.02-1.85 (6H, m),1.56-1.40 (1H, m).

Example 222-(4-(Diphenylmethyl)pyrazol-1-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid ##STR145##

By the same procedure as a series of reactions of example 1→example 2,the title compound having the following physical data was given by usingthe compound in reference example 4 and the compound obtained from thesame procedure as reference example 1, using methyl(2-hydroxymethyl-3,4-dihydronaphthalen-5-yloxy)acetate instead of methyl(2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate.

NMR: δ8.00 (1H, brs), 7.31-7.12 (11H, m), 7.06 (1H, s), 7.04 (1H, t,J=8Hz), 6.66 (1H, d, J=8Hz), 6.62 (1H, d, J=8Hz), 6.18 (1H, s), 5.35(1H, s), 4.78 (2H, s), 4.58 (2H, s), 2.84 (2H, t, J=8Hz), 2.13 (2H, d,J=8Hz).

Example 22(a)2-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid ##STR146##

By the same procedure as example 22, by using4-((3-pyridyl)phenylmethyl)pyrazole instead of the compound prepared inreference example 4, the title compound having the following physicaldata was given.

NMR: δ8.52 (2H, m), 7.60 (1H, m), 7.40-7.00 (10H, m), 6.69 (2H, d,J=8Hz), 6.23 (1H, s), 5.40 (1H, s), 4.80 (2H, s), 4.60 (2H, s), 2.89(2H, t, J=9), 2.14 (2H, t, J=9Hz).

The title compound thus obtained was further separated by highperformance liquid chromatography (ethanol:n-hexane=3:7; (containing0.5% acetic acid) to give each isomers having the following physicaldata.

(+) isomer: HPLC: t_(R) =67.93 min (ethanol:n-hexane=3:7; containing0.5% acetic acid);

α!_(D) +10.7 (c 0.7, chloroform).

(-) isomer: HPLC: t_(R) =77.33 min (ethanol:n-hexane=3:7; containing0.5% acetic acid);

α!_(D) -9.8 (c 0.8, chloroform).

Example 231-(2-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)ethylidene)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR147##

By the same procedure as a series of reactions of example 1→example 2,the title compound having the following physical data was given by using4-((3-pyridyl)phenylmethyl)pyrazole instead of the compound prepared inreference example 4 and the compound obtained from the same procedure asreference example 1, using methyl(1-(2-hydroxyethylidene)-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetateinstead of methyl(2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate.

NMR: δ8.65-8.42 (2H, m), 7.73-7.65 (1H, d, J=7Hz), 7.40-6.96 (11H, m),6.62 (1H, d, J=8Hz), 6.12 (1H, t, J=5Hz), 5.43 (1H, s), 4.82 (2H, d,J=5Hz), 4.61 (2H, s), 3.05 (2H, t, J=6Hz), 2.43 (2H, t, J=6Hz),1.82-1.68 (2H, m).

Example 242-(4-((1-Imidazolyl)phenylmethyl)pyrazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR148##

1) To a solution of the compound prepared in reference example 20 (480mg) in THF-methanol (2:1, 4 ml) was added 1N aqueous solution of sodiumhydroxide (2.0 ml) with stirring at room temperature. The mixture wasstirred for 30 min at room temperature. After neutralized by addition of1N hydrochloric acid (2.0 ml), the mixture was extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, and evaporated.

2) To a solution of the residue in methanol (4 ml) was added sodiumborohydride (100 mg) at 0° C. After stirred for 3 h at room temperature,the mixture was concentrated under reduced pressure. After the residuewas acidified by addition of 1N hydrochloric acid, the mixture wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate, and evaporated.

3) A solution of the residue in ethyl acetate-methanol (9:1, 3 ml) wascooled at 0° C. To the mixture was added excess amount of an etherealsolution of diazomethane. After standed for 10 min at room temperature,the mixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=5:2).

4) A mixture of the obtained compound (280 mg), imidazole hydrobromide(700 mg), molecular sieves 4A (1 g) and DMF (3 ml) was stirred for 5 hat 110° C. After cooled to room temperature, the mixture was dilutedwith n-hexane-ethyl acetate (1:1). The organic layer was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica gel column chromatography(methanol:chloroform=1:99→2:98→3:97).

5) By the same procedure as example 2, using the obtained compound, thetitle compound having the following physical data was given.

NMR: δ8.10-7.60 (2H, m), 7.42-7.06 (8H, m), 6.99 (1H, t, J=8Hz), 6.92(1H, s), 6.70-6.50 (2H, m), 6.45 (1H, s), 4.57 (2H, s), 4.15-3.90 (2H,m), 3.05-2.85 (1H, m), 2.74-2.18 (4H, m), 1.93-1.74 (1H, m), 1.46-1.20(1H, m).

Example 252-(5-Diphenylmethylisoxazol-3-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid ##STR149##

By the same procedure as a series of reactions of example 9→example 10,using the compound prepared in reference example 28, the title compoundhaving the following physical data was given.

NMR: δ7.40-7.02 (11H, m), 7.00 (1H, t, J=8Hz), 6.72 (1H, d, J=8Hz), 6.60(1H, d, J=8Hz), 5.60 (1H, s), 5.43 (1H, s), 4.53 (2H, s), 3.06-2.85(1H,m), 2.76-2.10 (4H, m), 1.95-1.75 (1H, m), 1.45-1.20 (1H, m).

Example 25(a) or (b)

By the same procedure as example 25, the compounds shown in thefollowing table 7 were given by using compounds prepared in referenceexample 32 and reference example 35 instead of the compound prepared inreference example 28.

                                      TABLE 7    __________________________________________________________________________    EX. No.         Structure of the example compound                                    NMR    __________________________________________________________________________    25(a)         7 #STR150##                δ 7.40-7.10(12H, m),   6.80(1H, d,                                    J=8Hz),   6.71(1H, d, J=8Hz),   5.82(1H,                                    s), 5.54(1H, s),   4.63(2H, s), 3.03-2.10                                      (7H, m), 1.98-1.73(1H, m),                                    1.45-1.22(1H, m).    25(b)         8 #STR151##                δ 7.40-7.10(10H, m),   7.02(1H, t,                                    J=8Hz),   6.80-6.55(4H, m),   5.67(1H,                                    s), 4.64(2H, s),   3.03-2.30(6H, m),                                    2.22-1.85(2H, m),   1.50-1.21(1H,    __________________________________________________________________________                                    m).

The example compounds shown in the table 7 are named as follows

25(a)2-(3-Diphenylmethylisoxazol-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

25(b)2-(3-Diphenylmethylisothiazol-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid

Example 26 1-(2-(4-Diphenylmethylpyrazol-1-yl)ethyl)indan-4-yloxy!acetic acid ##STR152##

By the same procedure as a series of reactions of reference example1→example 1→example 2, using methyl 1-(2-hydroxyethyl)-indan-4-yloxy!acetate instead of methyl(2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy)acetate, the titlecompound having the following physical data was given.

TLC: Rf 0.26 (chloroform:methanol=4:1);

NMR: δ7.37-7.10 (11H, m), 7.06 (1H, t, J=8Hz), 7.01 (1H, s), 6.80 (1H,d, J=8Hz), 6.58 (1H, d, J=8Hz), 5.34 (1H, s), 4.90 (1H, brs), 4.64 (2H,s), 4.22-4.08 (2H, m), 3.13-2.70 (3H, m), 2.45-2.12 (2H, m), 2.00-1.77(1H, m), 1.75-1.53 (1H, m).

Formulation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 5 mg of active ingredient.

    ______________________________________     2-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)methyl-3,4-                               500     mg    dihydronaphthalen-5-yloxy! acetic acid    Carboxymethylcellulose calcium                               200     mg    Magnesium stearate         100     mg    Microcrystalline cellulose 9.2     g    ______________________________________

Formulation Example 2

The following components were admixed in conventional manner. Thesolution was sterilized in conventional manner, placed 5 ml portion into10 ml ampoules and freeze-dried to obtain 100 ampoules each containing 2mg of the active ingredient.

    ______________________________________     2-(4-((3-Pyridyl)phenylmethyl)pyrazol-1-yl)methyl-3,4-                               200     mg    dihydronaphthalen-5-yloxy! acetic acid    Citric acid, anhydrous     20      mg    Distilled water            500     ml    ______________________________________

"While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof."

What we claim is:
 1. A fused benzeneoxyacetic acid derivative of theformula (I): ##STR153## R¹ is (i) hydroxy,(ii) C₁₋₁₂ alkoxy or(iii) NR²R³ ; R² and R³ each, independently, is(i) hydrogen atom or (ii) C₁₋₄alkyl or R² and R³ together with the nitrogen atom is an amino acid; R⁴each, independently, is(i) hydrogen atom, (ii) C₁₋₄ alkyl, (iii) phenylor (iv) C₁₋₄ alkyl substituted with one or two rings optionally selectedfrom 4-7 membered monocyclic hetero ring containing one or two nitrogenatoms, and phenyl; when R⁴ is phenyl or a group containing phenyl or a4-7 membered monocyclic hetero ring containing one or two nitrogenatoms, said phenyl and hetero ring may be substituted with one to threeof C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen atom, nitro group or trihalomethylgroup; e is 3-5; f is 1-3; m is 1 or 2; p is 1-4; q is 0-2; r is 1-4;and s is 0-3; with the provisos that,(1) when A is ##STR154## and R⁴ isa hydrogen atom, q or s is not zero; (2) when A is ##STR155## and R⁴ isa C₁₋₄ alkyl substituted with a hetero ring, a hetero ring in R⁴ isbonded to the alkyl via a carbon atom in the hetero ring; (3)--(CH₂)_(r) -- or ═CH--(CH₂)_(s) -- is bonded to the carbon atom at thea or b position of the ring; (4) and when A is ##STR156## R⁴ is a C1-4alkyl group substituted with one or two 4-7 membered monocyclic heterorings containing one or two nitrogen atoms; or non-toxic salts thereofor non-toxic acid addition salts thereof.
 2. The compound of claim 1,wherein R¹ is hydroxy.
 3. The compound of claim 1, wherein R¹ is C₁₋₁₂alkoxy.
 4. The compound of claim 1, wherein R¹ is NR² R³.
 5. Thecompound of claim 1, wherein ##STR157## wherein p and e have the samemeanings as in claim
 1. 6. The compound of claim 1, wherein ##STR158##wherein q and e have the same meanings as in claim
 1. 7. The compound ofclaim 1, wherein ##STR159## wherein r, f, a and b have the same meaningsas in claim
 1. 8. The compound of claim 1, wherein ##STR160## wherein s,f, a and b have the same meanings as in claim
 1. 9. The compound ofclaim 1, wherein R⁴ each, independently, is(i) hydrogen atom, (ii) C₁₋₄alkyl, (iii) phenyl, (iv) 7 membered, unsaturated monocyclic hetero ringcontaining one or two nitrogen atoms as hetero atom or (v) C₁₋₄ alkylsubstituted by one or two rings optionally selected from 7 membered,unsaturated monocyclic hetero ring containing one or two nitrogen atomsas hetero atom, and phenyl; with the proviso that at least one of R⁴should be the group containing the hetero ring as defined above.
 10. Thecompound of claim 1, wherein R⁴ each, independently, is(i) hydrogenatom, (ii) C₁₋₄ alkyl, (iii) phenyl, (iv) 6 membered, unsaturatedmonocyclic hetero ring containing one or two nitrogen atoms as heteroatom or (v) C₁₋₄ alkyl substituted by one or two rings optionallyselected from 6 membered, unsaturated monocyclic hetero ring containingone to two nitrogen atoms as hetero atom, and phenyl;with the provisothat at least one of R⁴ should be the group containing the hetero ringas defined above.
 11. The compound of claim 1, wherein R⁴ each,independently, is(i) hydrogen atom, (ii) C₁₋₄ alkyl, (iii) phenyl, (iv)4 or 5 membered, unsaturated monocyclic hetero ring containing one ortwo nitrogen atoms as hetero atom or (v) C₁₋₄ alkyl substituted by oneor two rings optionally selected from 4 or 5 membered, unsaturatedmonocyclic hetero ring containing one or two nitrogen atoms as heteroatom, and phenyl;with the proviso that at least one of R⁴ should be thegroup containing the hetero ring as defined above.
 12. The compound ofclaim 1, wherein R⁴ each, independently, is(i) hydrogen atom, (ii) C₁₋₄alkyl, (iii) phenyl or (iv) C₁₋₄ alkyl substituted by one or two ofphenyl.
 13. The compound of claim 10, which is 1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, 1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid, 1-2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)ethylidene-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid or2-(2-((3-Pyridyl)phenylmethyl)oxazol-4-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, or its methyl ester, or its octyl ester, or its acetamide,or its amide with glycine.
 14. The compound of claim 12, which is 2-3-((4-Diphenylmethyl)-1,2,3-triazol-2-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-((4-Diphenylmethyl)-1,2,3-triazol-1-yl)methyl-3,4-dihydronaphthalen-5-yloxy!acetic acid, 1- 2-((4-Diphenylmethyl) -1, 2,3-triazol-3-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy! aceticacid, 2-(1,2,4-Oxadiazin-5-yl) methyl-1, 2,3,4-tetrahydronaphthalen-5-yloxy! acetic acid, 2-2-(1,2,4-Oxadiazin-5-yl)ethenyl!1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-(1,2,4-Oxadiazin-5-yl)methyl-3,4-dihydronaphthalen-5-yloxy! aceticacid, 1-2-(1,2,4-Oxadiazin-5-yl)ethylidene!1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, 2-3-(3-Phenyl-1,2,4-oxadiazol-5-yl)propyl!2,3-dihydroinden-4-yloxy! aceticacid, 1-3-(5-Diphenylmethyl-1,2,4,oxadiazol-3-yl)-1-propenyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, 1-2-(5-Diphenylmethyl-1,2,4,oxadiazol-3-yl)ethyl!-3,4-dihydronaphthalen-5-yloxy!acetic acid, 1-2-(5-Diphenylmethyl-1,2,4,oxadiazol-3-yl)ethylidene!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-(4-Diphenylmethyl-1,2,3-triazol-2-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-(4-Diphenylmethyl-1,2,3-triazol-1-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-(4-Diphenylmethyl-1,2,3-triazol-3-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, 1-2-(3-Diphenylmethyl-1,2,4,oxadiazol-5-yl)ethyl!-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,2-(3-Diphenylmethyl-1,2,4,oxadiazol-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid,1-(2-(5-Diphenylmethyl-1,2,4,oxadiazol-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, or2-(3-Diphenylmethylisothiazol-5-yl)methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy!acetic acid, or its methyl ester, or its octyl ester, or its acetamide,or its amide with glycine.
 15. A pharmaceutical composition whichcomprises, as active ingredient, an effective amount of a fusedbenzeneoxyacetic acid derivative of the formula (I) of claim 1 or anon-toxic salt thereof, or a non-toxic acid addition salt thereof, witha pharmaceutical carrier or coating.
 16. A method for preventing ortreating thrombosis, arteriosclerosis, ischemic heart diseases, gastriculcer or hypertension, comprising, administering to a host in need ofsuch prevention or treatment an effective amount of a fusedbenzeneoxyacetic acid derivative of the formula (I) of claim 1 or anon-toxic salt thereof, or a non-toxic acid addition salt thereof.